Renal abscess complicating acute pyelonephritis in children: Two cases report and literature review

Rationale: To describe the diagnostic and treatment approaches of renal abscesses complicated with acute pyelonephritis in children. Patient concerns: Two children presented with fever, vomiting, and abdominal pain with no typical manifestations, like frequent urination, urgency, dysuria, hematuria, foam urine, and lumbago. Renal abscess complicating acute pyelonephritis was diagnosed by B-ultrasound and computed tomography enhancement. Moreover, inflammatory markers were elevated significantly, but routine blood and urine cultures were repeatedly negative. The empirical anti-infection therapy had no obvious effect. A pathogenic diagnosis was confirmed in case two, and macro gene detection in blood and urine guided the follow-up treatment. Diagnoses: Both children were diagnosed with acute gastroenteritis on admission, but renal abscess complicating acute pyelonephritis were diagnosed by imaging examination. Interventions: Both children were given anti-infection therapy of third-generation cephalosporin, which had no obvious effect. Routine blood and urine cultures were repeatedly negative. Case one was changed to piperacillin sodium tazobactam. We further carried out blood and urinary metagenomic next-generation sequencing detection for case two. Meanwhile, meropenem and linezolid anti-infection treatment was given. The results showed overlapping infection with Escherichia coli and Enterococcus faecalis. According to the genetic test results, amoxicillin clavulanate potassium combined with nitrofurantoin were prescribed after discharge. Outcomes: Clinical symptoms of the 2 children disappeared, the infection was controlled, and imaging showed that renal abscess complicated with acute pyelonephritis disappeared. Lessons: The clinical spectrum of renal abscess complicating acute pyelonephritis is vague, with no specific manifestations, and can be easily misdiagnosed. B-ultrasound and computed tomography enhancement are helpful in making a definite diagnosis. Moreover, the sensitivity of routine culture is low, and metagenomic next-generation sequencing might be helpful to detect pathogenic microorganisms and guided treatment. Early treatment with broad-spectrum antibiotics might have favorable outcomes.


Introduction
Kidney abscess in children is a rare but serious condition that might lead to serious morbidities. [1]It is often complicated by acute pyelonephritis that is characterized by an acute onset, serious illness, and nonspecific clinical manifestations.It can easily be misdiagnosed, and the prognosis might be delayed when treatment is delayed, leading to bacteremia and renal scarring, or even renal insufficiency that might require nephrectomy, causing a great harm to affected children. [2,3]In this article, 2 cases of children with acute pyelonephritis complicated with renal abscesses were retrospectively collected and described.Both cases presented with nonspecific manifestations and a systemic inflammatory reaction.Moreover, we conducted a literature review to summarize the clinical characteristics, diagnosis, treatment, and prognosis of similar cases to improve clinical practice.

Case one
A 4-year-old girl presented at Xiamen Children's Hospital with fever, vomiting, and abdominal pain on June 7, 2021.Fever occurred 1 day ago, with a peak of 39.8°C.Half a day ago, vomiting was associated with paroxysmal abdominal pain that was relieved yellow watery mucus-free stool.Other manifestations also included frequent micturition, urgency, pain, dysuria, hematuria, and foamy urine, with no recent history of trauma, contacting other patients or traveling abroad.Physical examination showed body temperature to be 38.9°C, with stable vital signs.Other manifestations also included painful expression, forced posture, slight tension of abdominal muscles, refusal to press, total abdominal tenderness, and no rebound pain, Laboratory evaluation showed leukocytosis and inflammatory markers were significantly increased (white blood cell count [WBC] 31.48 × 10 9 /L, neutrophil count [NEU] 28.88 × 10 9 /L, C-reactive protein [CRP] 186.18 mg/L, procalcitonin 19.71 μg/L) (Fig. 1A and B).Urine analysis showed that protein was 2+ mg/L, but no white or red blood cells were found.Biochemical parameters were also assessed (creatine kinase-MB 72 U/L, brain natriuretic peptide 265 pg/mL, creatinine 48 μmol/L, and urea nitrogen 4.5 mmol/L).Stool examination, erythrocyte sedimentation rate (ESR), and tumor markers were normal.Moreover, microbiological tests, include blood, urine, and fecal cultures.Since the child had no previous history of specific diseases, immune assessment assays were conducted.The results showed that the immunoglobulin level was low, with IgA 0.463 g/L (normal value 0.52-2.16g/L), IgG 5.74 g/L (normal value 6.09-12.85g/L), and IgM 0.606 g/L (normal value 0.67-2.46g/L).On the other hand, T cell subsets were normal.
On the second day, urinary ultrasound detected the right renal abscess (0.94 cm × 0.93 cm in size, Fig. 1C).After admission, intravenous ceftriaxone sodium (80 mg/kg/d 6.8) was given, but the clinical manifestations and inflammatory indicators did not improve.Therefore, ceftriaxone was replaced by piperacillin sodium tazobactam (337.5 mg/kg/d 6.8-6.30).Complete abdominal computed tomography (CT) enhancement on day 6 after treatment showed right pyelonephritis with renal abscess formation (Fig. 1E).After 1 week of treatment, the body temperature dropped to be normal and stable.On the 10th, 15th, and 23rd days, renal ultrasound examination was performed to monitor the size of right renal abscess (Fig. 1D and F), which completely subsided (Fig. 1G) and the patient was discharged from hospital.

Case two
A 4-year-old boy presented to Xiamen Children's Hospital with fever and abdominal pain for 2 days on July 30, 2021.
Fever occurred 2 days ago, with a peak of 39.0°C.Paroxysmal abdominal pain, vomiting once, with no diarrhea, no frequent urination, urgency, pain, hematuria, and foam urine were also reported.Routine blood tests showed WBC 14.65 × 10 9 /L, NEU 11.85 × 10 9 /L, CRP 246.7 mg/L, and the colored Doppler ultrasound of gastrointestinal tract was normal.The patient had a history of urinary tract infection (UTI) at the age of 1 year and 6 months.Physical examination showed body temperature to be 39.0°C, with stable vital signs.He complained of abdominal distention with tenderness, and no rebound pain.In-hospital laboratory evaluation showed leukocytosis and elevated inflammatory markers (WBC 12.47 × 10 9 /L, NEU 9.80 × 10 9 /L, CRP 202.43 mg/L; procalcitonin 16.81 μg/L; ESR 74 mm/hr) (Fig. 2A  and B).Urine routine showed a pathological cast + μL, occult blood 3 + mg/L, red blood cells 3-5/HP, white blood cells 5-10/ HP, and protein 2+.The routine, biochemical, ESR, tumor markers, anti-O, humoral immunity, and T cell subsets were all normal.Moreover, microbiological tests, like blood, urine, and fecal cultures, G test, GM test, T-Spot, were all negative.Urinary color Doppler ultrasound indicated diffuse damage of both kidney and nephritis was suspected, with a slightly thickened bladder wall.
After admission, bacterial infection was considered due to significantly elevated inflammatory markers.Ceftriaxone (80 mg/kg/d 7.30-7.31)was given intravenously, but the symptoms did not improve.After reexamination, the inflammatory index was higher than before.Two days later, the plain CT scan of the whole abdomen showed that both kidneys were enlarged and uneven in density, suggesting inflammatory changes.Ceftriaxone was replaced by cefoperazone sulbactam sodium (240 mg/kg/d 8.1-8.5).On the 4th, 9th, 12th, 18th, and 24th day after treatment, continuous renal ultrasound examination showed that a decreasing pattern in the size of the renal abscess was 0.65 cm (Fig. 2E), 0.8 cm, 2.0 cm × 1.4 cm (Fig. 2F), 2.0 cm × 1.3 cm (Fig. 2G), 0.7 cm, 0.8 cm (Fig. 2H), until it disappeared, with only right renal parenchyma inflammation on the 24th day (Fig. 2I).On the 20th day, CT enhancement of the whole abdomen showed bilateral pyelonephritis, and the right kidney was prominent (Fig. 2J).One week after treatment, the inflammatory index improved, but the body temperature did not.Therefore, the macro gene detection in blood and urine was approached to clarify the etiology.Moreover, cefoperazone sulbactam sodium was replaced by meropenem (60 mg/ kg/d 8.6-8.23)combined with linezolid (30 mg/kg/d 8.6-8.23).Combined with the pathogenic results of the macro gene detection in blood and urine (Table 1), amoxicillin clavulanate potassium (685.5 mg/kg/d 8.24-10.5)combined with nitrofurantoin (6.66 mg/kg/d, 8.24-10.5)were prescribed after discharge.
After treatment, antibiotics were stopped after the routine urine test and urinary color Doppler ultrasound were normal on October 5, 2021.However, 1 week later (October 12, 2021), fever and abdominal pain recurred in the child.Color ultrasound of urinary system suggested recurrence of renal abscess, and was hospitalized again.Laboratory evaluation showed leukocytosis and elevated inflammatory markers (Fig. 2C and  D).He was given intravenous piperacillin sodium tazobactam (337.5 mg/kg/d) for 2 weeks and was discharged after improvement.Furthermore, considering that the child suffered from renal abscess twice in a short time, the excretory urography was performed with the consent of family members to evaluate whether there are urinary system abnormalities such as ureteral obstruction and vesicoureteral reflux.This indicated that the right vesicoureteral reflux was grade II.Renal static imaging (dimercaptosuccinic acid) showed pyelonephritis, right kidney scar, and impaired right renal function (71.68% for left kidney and 28.32% for right kidney).Urinary magnetic resonance imaging/MRU showed multiple wedge-shaped diffusion-restricted shadows in the parenchyma of both kidneys indicating inflammation.It also showed a larger left kidney (the upper and lower diameters of the left kidney were about 9.0 cm long and www.md-journal.comthe upper and lower diameters of the right kidney are about 6.7 cm long).

Discussion
The exact etiology and pathogenesis of renal abscess in children are not clear.Estimates show that children with renal abscess often have abnormal ureters (41.2%), renal dysplasia or nonfunctional kidneys (17.6%), vesicoureteral reflux (11.8%), and other genitourinary system abnormalities. [1,10]Moreover, 23.5% of these children usually have a history of repeated lower UTIs, [22] suggesting that these events might predispose to developing renal abscesses.We presented case two with a history of UTIs, and 2 renal abscesses.Dimercaptosuccinic acid showed pyelonephritis, right kidney scar, and impaired function.Considering the possibility of urinary tract abnormalities such as abnormal ureter and vesicoureteral reflux, the excretory urography was improved, and the results showed that the right vesicoureteral reflux was grade II, which indicated our expectations that were based on physical and clinical evaluation.However, case one had no previous history of UTIs and other systemic infections.Because the family members refused to take cystourethrography examination, it was not clear whether there were urogenital malformations, like vesicoureteral reflux.However, its humoral immune indexes (IgA, IgG, IgM) were low, suggesting that immune assays might be used to predict renal abscesses in these children.Therefore, assessment of immune assays should be considered in children with suspected renal abscesses.
Renal abscess might develop secondary to different routes, including ascending urinary tract and hematogenous infections, and the spread of inflammation from the adjacent organs.Different routes of infection might introduce various pathogenic bacteria.Upward infection is often associated with urogenital malformation or repeated UTIs.The main pathogenic bacteria are gram-negative bacteria, mainly E coli.Moreover, Staphylococcal infection is the most common cause of hematogenous spread. [23,24]Abscess is often complicated by a severe inflammatory reaction, but the sensitivity rate of routine blood culture is extremely low.Our literature review findings demonstrated that in children with renal abscess, the blood culture positive rate was only 6%, suggesting that hematogenous dissemination may not be the main mechanism of childhood renal abscess, as indicated in our 2 cases.After 1 week of treatment with third generation cephalosporin, no improvement was noticed in case two.Therefore, metagenomic next-generation sequencing (mNGS) for detecting blood and urine pathogens was carried out.Even after 1 week of treatment with third generation cephalosporins, E coli and Enterococcus faecalis were still detectable, which is consistent with previous results that E coli is the main pathogen of renal abscess caused by upward infection, providing a pathogenic reference for subsequent antibiotic sequential treatment.Moreover, using mNGS technology might be helpful to clarify the etiology and enhance choosing the most sensitive treatment regimen.mNGS is a new tool that can directly perform high-throughput sequencing on nucleic acids in samples to identify potential pathogens quickly and accurately. [25]Various types of specimens can be tested, including cerebrospinal fluid, pleural, peritoneal and joint cavity effusions, alveolar washings, sputum, concentrated juice, blood, and tissues.The modality is less affected by antibiotic use, [26] which improves is sensitivity, and is recommended for the diagnosis of acute and critical conditions and detecting difficult infections. [27][30][31][32][33][34] However, there is a lack of data regarding the efficacy of mNGS detection in identifying the causative organism of renal abscess.As far as we know, this is the first report to do so.
The clinical manifestations of renal abscess in children lack specificity.Fever is the most common manifestation, and some children can show typical urinary symptoms such as foam urine, hematuria, turbid urine, frequent urination, urgency, and pain.However, for older children, there are few typical urinary symptoms, but atypical symptoms such as lumbago, abdominal pain, nausea, and vomiting might also be detected. [4,7,9]Moreover, physical examination might show abdominal tenderness, rebound pain, or the presence of an abdominal mass.Therefore, the diagnosis of this condition might be misleading and further measures are required to establish a proper differential diagnosis.
The 2 children admitted to our hospital were mainly characterized by fever, vomiting, and abdominal pain.They were  Xu YQ et al [5]  Chen CY et al [6] Chen CY et al [7] 17 17  Enterococcus    Note: [6,7]  The kidney abscess data described in these 2 articles came from the same center.

Figure 1 .
Figure 1.The changes of clinical indexes, kidney B-ultrasound, computed tomography (CT) before, and after treatment in case one.(A) Changes of white blood cell counts, neutrophil counts, and body temperature in case one.The white blood cell counts and neutrophil counts were significantly increased on admission, and the body temperature was repeatedly high, which decreased to normal after anti-infection treatment.(B) Changes of CRP and PCT in case one.The levels of CRP and PCT were significantly increased on admission, and went back to normal after anti-infection treatment.(C, D, F, and G) Renal ultrasonography was performed on the 2nd, 10th, 15th, and 23rd day after admission for case one.The abscesses of the right kidney were measured as 0.94 cm × 0.93 cm, 1.53 cm × 0.82 cm, 3.7 cm × 2.1 cm × 4.3 cm (arrow), and the abscesses were completely subsided on day 23.(E) Enhanced CT scan performed on day 6 of admission showed abnormal enhancement in the upper pole and middle of the right kidney, suggesting pyelonephritis with renal abscess formation (arrow).CRP = C-reactive protein, PCT = procalcitonin.

Figure 2 .
Figure 2. The changes of clinical indexes, kidney B-ultrasound, computed tomography (CT) before, and after treatment in case two.(A and C) Changes of white blood cell counts, neutrophil counts, and body temperature at the first (A) and second (C) hospitalization in case two.The white blood cell counts and neutrophil counts were significantly increased on admission, and the body temperature were high, which returned to normal after anti-infection treatment.(B and D) Changes of CRP and PCT at the first (B) and second (D) hospitalization in case two.The levels of CRP and PCT were significantly increased on admission, and decreased to normal after anti-infection treatment.(E-I) Renal ultrasonography was performed in case two on the 4th, 9th, 12th, 18th, and 24th day after the first admission.The abscesses of the right and left kidney were measured as 0.65 cm, 2.0 cm × 1.4 cm, 2.0 cm × 1.3 cm, 0.7 cm, and 0.8 cm (arrow).(J) Enhanced CT scan performed in case two on day 20 of the first admission showed bilateral pyelonephritis with right kidney protrusion (arrow).CRP = C-reactive protein, PCT = procalcitonin.

Table 1
mNGS report of bacteria and virus in blood and urine.

Table 2
Summary of literature review findings.